CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia.
CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia.
复制标题
CAY10683和伊马替尼在慢性粒细胞白血病中通过抑制HDAC2克服伊马替尼耐药具有协同作用
作者：
伊马替尼(IM)用于靶向bcr-abl融合蛋白，因此，慢性粒细胞白血病(CML)被认为是一种可治愈的疾病，患者可以获得长期生存。然而，15%-20%的CML病例最终会出现IM耐药，并将发展到加速期，最终导致爆发危机，从而限制了治疗选择，并导致令人沮丧的存活率。组蛋白脱乙酰酶(HDACs)被发现可以调节癌基因和抑癌基因的活性，在肿瘤的发生中起着关键作用。最近发现IM联合HDAC抑制剂(HDACi)可以作为克服CML患者IM耐药的一种有前途的方法。Santacruzamate A(CAY10683)已被开发为一种选择性强的抗HDAC2的HDACi。因此，在本研究中，我们旨在探讨CAY10683联合IM能否作为治疗IM耐药的CML的候选药物。研究CAY10683与IM联合应用对IM耐药CML细胞的细胞周期停滞、细胞凋亡及细胞活力的影响，发现CAY10683与IM联合治疗对IM耐药具有协同作用。进一步研究表明，CAY10683联合IM主要通过抑制耐IM的K562-R和LAMA84-R细胞中的HDAC2而发挥协同作用。此外，PI3K/Akt信号转导通路参与了IM耐药CML细胞的HDAC2调控。最终，在异种移植小鼠模型的基础上，人们还发现，联合治疗显著抑制了体内CML的增殖。综上所述，本研究结果表明CAY10683联合IM有可能作为治疗IM耐药的CML的候选药物。伊马替尼(IM)用于靶向bcr-abl融合蛋白，因此，慢性粒细胞白血病(CML)被认为是一种可治愈的疾病，患者可以获得长期生存。
Imatinib (IM) is utilized for targeting the BCR–ABL fusion protein and as such, chronic myeloid leukemia (CML) is considered to be a curable disorder for which patients can achieve a long survival. However, 15–20% CML cases end up with IM resistance that will develop into the accelerated stage and eventually the blast crisis, thereby restricting the treatment choices and giving rise to a dismal survival rate. Histone deacetylases (HDACs) have been identified to modulate the oncogene as well as tumor suppressor gene activities, and they play crucial parts in tumorigenesis. It is found recently that IM combined with HDAC inhibitors (HDACi) can serve as a promising means of overcoming IM resistance in CML cases. Santacruzamate A (CAY10683) has been developed as one of the selective and powerful HDACi to resist HDAC2. Therefore, in this study, we aimed to examine whether CAY10683 combined with IM could serve as the candidate antitumor treatment for CML cases with IM resistance. The influences of CAY10683 combined with IM on the cell cycle arrest, apoptosis, and viability of CML cells with IM resistance were investigated, and it was discovered that the combined treatment exerted synergistic effects on managing the IM resistance. Moreover, further studies indicated that CAY10683 combined with IM mainly exerted synergistic effects through inhibiting HDAC2 in K562-R and LAMA84-R cells with IM resistance. Besides, the PI3K/Akt signal transduction pathway was found to mediate the HDAC2 regulation of CML cells with IM resistance. Eventually, it was also discovered, based on the xenograft mouse model, that the combined treatment dramatically suppressed CML proliferation in vivo. To sum up, findings in the current study indicate that CAY10683 combined with IM can be potentially used as the candidate treatment for CML with IM resistance. Imatinib (IM) is utilized for targeting the BCR–ABL fusion protein and as such, chronic myeloid leukemia (CML) is considered to be a curable disorder for which patients can achieve a long survival.
登录
查看更多内容
影响因子：
6.6
作者：
Chorzalska A;Ahsan N;Rao RSP;Roder K;Yu X;Morgan J;Tepper A;Hines S;Zhang P;Treaba DO;Zhao TC;Olszewski AJ;Reagan JL;Liang O;Gruppuso PA;Dubielecka PM
通讯作者：
Dubielecka PM
影响因子：
5.7
作者：
Matsuda Y;Yamauchi T;Hosono N;Uzui K;Negoro E;Morinaga K;Nishi R;Yoshida A;Kimura S;Maekawa T;Ueda T
通讯作者：
Ueda T
影响因子：
11.2
作者：
Donato, NJ;Wu, JY;Talpaz, M
通讯作者：
Talpaz, M
影响因子：
5.4
作者：
Lin, Pei-Pei;Hsieh, You-Miin;Tsai, Cheng-Chih
通讯作者：
Tsai, Cheng-Chih
影响因子：
9.7
作者：
Jiang, Xue-Jie;Huang, Kai-Kai;Meng, Fan-Yi
通讯作者：
Meng, Fan-Yi